Safety tops concerns in drive to develop, distribute COVID-19 vaccines
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While experts are optimistic that multiple COVID-19 vaccine products will be available in late 2020 or early 2021, ongoing questions remain surrounding safety, ethics and distribution, according to panelists at ACR Convergence 2020.
The first question posed to panelist Grace Lee, MD, of Stanford University, dealt with ensuring the safety of a vaccine in an accelerated development environment. Before giving an exhaustive review of the “bedrock” of safety protocols in place for the COVID-19 vaccine development process, she commented on the hard reality of the situation.
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“We could wait a year to have all the information we need and all of the safety data we need,” she said. “But the tradeoff is that we lose that time of vaccinating. We have to continue to monitor [safety outcomes and data] in real time.”
That monitoring bedrock is rigorous, according to Lee. The data safety monitoring board (DSMB) oversees the process from clinical trials to submission to the FDA. The Vaccines and Related Biological Products Advisory Committee (VRBPAC) weighs in before the product and data go to the Advisory Committee on Immunization Practice (ACIP) for consideration. “The ACIP advises the director of the CDC on use of the vaccine in a civilian population,” Lee said.
The Vaccine Adverse Event Reporting System (VAERS) gathers relevant data, as does the National Healthcare Safety Network (NHSN), while the CDC’s vaccine safety program (V-SAFE) and even the department of defense (DOD) may be involved.
VAERS, in particular, can be extremely useful as a data gathering entity, according to Lee. “Anyone can contribute data to VAERS,” including health care personnel, patients, parents of patients, industry or other relevant parties, she said. “The important thing is to be able to capture as much information as possible.”
The endgame for all these efforts is to reinforce trust in the vaccine development process, according to Lee. This starts with promoting confidence for health care providers to get themselves vaccinated and continues through engaging communities, patients and patient advocacy groups. “We are going to need all hands on deck to help us monitor safety,” Lee said.
The good news is that the trials for COVID-19 vaccines in development in the U.S. are “huge,” according to Lee, often involving between 30,000 and 60,000 participants. “We will have more safety data prior to approval than we do for many other vaccines going to the FDA for approval,” Lee said. “We are not taking any shortcuts. This will enhance and promote trust in the vaccine decision making process.”
Promising candidates, big numbers
Speaking of huge numbers, Dan Barouch, MD, PhD, of Beth Israel Deaconess Medical Center and Harvard Medical School, said that there are “over 200” vaccine candidates in development worldwide. “This is truly astonishing and a testament to science,” he said.
Ten to 12 of those products are in phase 3 trials, including four that are currently in phase 3 in the U.S., and two more that will enter that phase “hopefully” this year, Barouch said.
Barouch believes that the mRNA products from Moderna and Pfizer are “likely to yield results as soon as this month.”
Two adenovirus vector vaccines — one from AstraZeneca and one from Johnson & Johnson — are also in phase 3.
“Our hope is that before the end of this calendar year, two protein-based products will start phase 3 trials,” Barouch said. “But there is some uncertainty about that.”
If there is another issue pertaining to big numbers, it will be distribution of vaccine products to billions of people worldwide. For example, some vaccine products will require “cold chain” storage, meaning they will need to be refrigerated at subzero temperatures almost until the time it goes into an individual’s arm. This will present enormous logistical challenges in hard-to-reach areas in the U.S. and in countries in the developing world with limited resources.
Moreover, the global health care community must determine how to prioritize vaccine distribution. While the U.S. has created a hierarchy of need — health care workers, front line workers, the elderly, those with comorbid conditions and then on to the general population — whether that will come to pass, or whether such a pattern will be followed on a worldwide scale remains to be seen.
Ethical considerations
Distribution challenges are just part of the “highly politicized” environment surrounding vaccines, according to Jimmy Kolker, MPA, of Georgetown University. Kolker, who, as an ambassador represented the United States at the WHO and other such organizations, said that Americans should have “huge confidence about widespread use of a vaccine,” but acknowledged that misinformation, vaccine hesitancy and stumbling blocks in the rollout of candidates can undermine that confidence.
While Kolker acknowledged the safety measures taken in the development process outlined by Lee, he raised the question of whether a faster timeline would allow for all people of all races and ethnicities, or elderly or other high-risk populations, to be “adequately represented” in these large trials. In addition, should a patient on a clinical trial develop COVID-19, uncertain treatment paradigms do not ensure recovery. “The ethics of that are unclear.”
Moreover, while the U.S. is attempting to be transparent with its vaccine development program, that may not be the case in Russia, China or many of the other countries developing one of those 200 potential candidates. “Suddenly, this tiny niche of health diplomacy [has moved into] unchartered territory,” Kolker said.
While there may be concerns with any individual vaccine product, Barouch believes that having multiple candidates moving to the market will be beneficial in covering more people domestically and abroad. “Some will be easier to deploy, some will be easier to manufacture, some will have different adverse event portfolios,” he said, stressing that the more options, the better.
Use in rheumatology populations
If there is one other group that should be represented strongly in vaccine development trials, it is those with rheumatologic or autoimmune conditions, according to Leonard Calabrese, DO, chief medical editor of Healio Rheumatology and head of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic. He addressed the “big question” about how the vaccine products in development may affect these patient populations.
“These big phase 3 trials are basically looking at relatively healthy people across an age spectrum that is highly desirable,” he said. “Not surprisingly, patients with active autoimmune diseases are censored. Those on immunosuppression are censored.”
It is for these reasons that Calabrese described a stark reality that is likely to face rheumatologists and their patients when COVID-19 vaccines hit the market. “We will go into this without any obvious data,” he said.
Despite this concern, Calabrese believes that rheumatology patients “respond pretty darn well to vaccines,” regardless of whether they are T-cell dependent or independent.
Barouch said clinical trials will not always exclude patients with rheumatologic and autoimmune diseases. He suggested that these patients may ultimately be represented in smaller studies, or they will be included in bigger phase 3 trials. “If not in a dedicated efficacy study, because that might be impractical, [they will be studied] at least for safety and immunogenicity,” he said.
Regardless of the type and level of data available when vaccines emerge, Calabrese urged doctors to be doctors. “If COVID-19 has taught us one thing, it is the cruel lesson that we have had to make medical decisions based on imperfect data from the beginning,” he said, citing ongoing experimental use of antivirals and interleukin-6 inhibitors, with mixed results.
“It is about being a good doctor,” Calabrese said. He stressed that rheumatologists should share “science and empathy.”
Explaining potential risks clearly and honestly is critical. In addition, reading the patient may also aid in clinical decision making. For example, some patients may feel young or strong enough to withstand COVID infection, while others may be “hunkered down” and confident in their ability to social distance, according to Calabrese.
For patients who are vaccine-hesitant, Calabrese said he may listen to that patient’s concerns and simply wait until more data emerges before attempting the conversation again. “In our own little microcosms, we will make those decisions for ourselves,” he said.
If there is a “small elephant in the room,” it is whether the vaccine may cause a flare in an underlying autoimmune condition, according to Calabrese. Protein-based vaccines have not posed that risk previously, but he suggested that “it is something we should keep an eye on.”
In closing, Calabrese called on the rheumatology community to meet any challenges that arise. “We as a profession, as rheumatologists in the U.S. and around the world, need to up our game in vaccine health and administration,” he said. “It is going to be difficult. Let’s do our part.”
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Barouch D, Calabrese L, Kolker J, Lee G. Developing, Deploying and Distributing COVID-19 Vaccines: Challenges and Opportunities. Presented at: ACR Convergence 2020; November 5-9, 2020 (virtual meeting).
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